Penem antibiotics represented by thienamycin have attracted attention as medicines because of their broad antimicrobial spectra.
Various processes for preparing penem antibiotics have been reported, e.g., in Kametani, Heterocycles, Vol. 17, pp. 463-506 (1982) and Shibuya, et al., Yuki Gosei Kaoaku, Vol. 41, p. 62 (1983). Among the known processes, a process using a 4-acyloxyazetidinone or a derivative thereof represented by formula (IV) as an intermediate is particularly advantageous in that the compound of formula (IV) is reactive with various nucleophilic agents, leading to various penem antibiotics.
Known processes for preparing the intermediate compound of formula (IV) include oxidation of 4-carboxyazetidinone derivatives with lead tetraacetate (Tetrahedron Letters, Vol. 23, p. 2293 (1982), electrode oxidation of 4-carboxyazetidin-one derivatives (Tetrahydron Letters, Vol. 29, p. 1409 (1988)), oxidation of 4-acetylazetidinone derivatives with m-chloro-perbenzoic acid (JP-A-61-50964) (the term "JP-A" as used herein means an "unexamined published Japanese patent application"), and treatment of 4-silyloxyazetidinone derivatives with acetic anhydride (European Patent 247,378).
In order to introduce an acetoxy group to the 4-position of the azetidinone skeleton according to any of the above-described processes, it is necessary to synthesize an azetidinone compound having a specific substituent group at the 4-position, via which an acetoxy group is to be introduced. However, preparation of an azetidinone compound having such a specific substituent group at the 4-position involves complicated steps and, also, it has been difficult to convert the substituent group at the 4-position to an acetoxy group. Hence, these conventional processes are not regarded advantageous as industrial techniques.
Other processes for synthesizing 4-acyloxyazetidinone derivatives are described in JP-A-3-48681 and JP-A-3-56481, but they have industrial disadvantages such as low yields, in addition to the above-described problems.
On the other hand, it has lately been suggested to react an azetidinone compound with acetic acid and a peroxide as an oxidizing agent in the presence of a ruthenium compound catalyst to introduce an acetoxy group as disclosed in JP-A-2-231471. However, many of peroxides useful as an oxidizing agent are generally dangerous, demanding meticulous care not only in storage and transportation but on actual use. Besides the safety problem, they are expensive.
Further, 4-acetoxyazetidinone derivatives are still unsatisfactory due to the insufficient activity of the 4-positioned acetoxy group as a releasable group, and it is desired to develop an intermediate having a more active releasable group. It is known that the activity of a releasable group increases and becomes more advantageous in the displacement reaction at the 4-position according as its acidity increases (see W. N. Speckamp and H. Hiemstra, Tetrahedron, Vol. 41, p. 4367 (1985)). From this point of view, it is anticipated that a chloroacetoxy group, a cyanoacetoxy group, a bromoacetoxy group, a dichloroacetoxy group, a dibromoacetoxy group, and the like are more active than an acetoxy group.
In particular, while carbon nucleophilic agents used in reactions for forming a carbon-to-carbon bond by using a Lewis acid, etc., such as ketene silyl acetal and silyl enol ether, are relatively labile under the reaction conditions, such lability would be compensated for by increasing the reaction rate by using an intermediate with the above-mentioned active releasable group. Nevertheless, it has been difficult to synthesize such an intermediate from 4-acetoxy compounds through conventional techniques such as ester exchange reaction.